The management of hair loss has been addressed using topical antihypertensive agents such as minoxidil. V. H. Price, J. Amer. Acad. Dermatology, 16, 749-750 (1987). Minoxidil enlarges vellus hair follicles and seems to maintain terminal follicles in the scalps of mammals. After four months of treatment, approximately 25% of patients achieve minimal regrowth of hair. Rogaine.RTM., the only compound approved to date to treat baldness, was developed because the oral administration of the drug stimulated hair growth. (Upjohn Co. Physicians Desk Ref., pp. 2578, 49th Ed (1995). Minoxidil is a substituted pyrimidine. The present invention relates to the use of daidzein, known as 7-hydroxy-3-(4-hydroxyphenyl)-4-H-1-benzopyranyl-4-one. Daidzein is an isoflavone with a variety of pharmacological effects.
Along with isoflavone glycosides, such as daidzin (7-glycoside daidzein), isoflavones are found mostly in leguminous plants. (J. L. Ingham, Naturally Occurring Isoflavonoids, Vol. 43, pp. 1-226, Progress in the chemistry of organic natural products, Ed, W. Herz, H. Grisebach & G. W. Kirby, Springer-Verlag, Wien, New York, 1983). The synthesis of daidzein & its derivatives was reviewed & reported by G. Shao et al (Yao Hsueh Hsueh Pao 15(9), 538, 1980; Q. E. Ji and Y. L. Wei, Yao Hsueh Hsueh Pao 24(12), 906, 1989). They demonstrated that some of these isoflavones protected mice from hypoxia and increased their coronary blood flow. Some of the isoflavones including daidzein tested negative in mutagenicity using the Salmonella and mammalian microsomal assay (R. M. Bartholomew, D. S. Ryan, Mutat. Res. 78(4), 317, 1980).
Synthetically made daidzein was approved as a pharmaceutical agent in China in 1986 (Health Bureau of Liao Ning Province Approved Drug number; (86)772-2-2). The main indication is hypertension.
Daidzein and its derivatives were also shown to have estrogenic effects (E. Farmakalidis, Food Chem, Toxicol 22,237, 1984). In a recent study, daidzein, equol and lignan were found to compete with estradiol for binding to the rat uterine type II estrogen binding site (H. Aldercreutz et al, J. Steroid Biochem. Mol. Biol. 41(3-8): 331, 1992) and to human recombinant estrogen receptor (ibid 49(2-3): 153, 1994). The estrogenic effects are very mild and become significant only with high doses or prolonged treatment. G. H. Degan (J. Steroid Biochem 35(3-4): 473, 1990) reported that daidzein and three other isoflavones stimulated microsomal prostaglandin synthetase.
Y. Jing et al (Anti-cancer Research 13(4): 1049, 1993) reported that greater than 10 .mu.g/ml of daidzein inhibited the growth of HL60 human leukemia cells. The potent differentiation inducing activity of daidzein was also recently reviewed by R. Han (Chinese Medical Sciences. J.9(1): 61, 1994). Isoflavones, genistein, biochanin A, but not daidzein, inhibited both serum and epidermal growth factor-stimulated growth of LNCaP and Du-145 human prostate cancer cell lines.
Daidzein was also shown to inhibit insulin or insulin growth factor-1 (IGF-1)-mediated signaling in cell cycle progression of Swiss 3T3 cells. It was suggested that the blocking of the G1 phase cell cycle was attributed to the inhibition of casein kinase II enzyme activity by daidzein. The enzyme is required for the commitment of mitogenic signal by insulin or IGF-1 in G1 phase. (K. Higashi and H. Ogawara, Biochim et Biophysica Acta 1221(1): 29, 1994).
Isoflavones have been claimed to exhibit antifibrile, antispasmodic, antihypertensive, and anti-dysrhythmic activities. Until recently, an effect of isoflavones on ethanol drinking behavior had never been demonstrated. In 1993, W-M Keung and B. L. Vallee published a series of studies on the implication of isoflavones, especially daidzin and daidzein, in the treatment of alcohol abuse. They found that daidzin and daidzein suppressed free choice ethanol intake, and did not significantly affect the body weight, water or food intake of Syrian Golden hamsters tested (W-M Keung and B. L. Vallee, PCT Patent Publication No. W093/00896; Proc. Natl. Acad. Sci. USA 90:10008, 1993). This work was based on the use of folklore herbal medicine, Radix puerariae (RP) prepared from the root of leguminosae Pueraria lobota (commonly known as kudzu), for anti-drunkenness effect. RP is a rich source of isoflavones. Daidzein and genistein, isolated from RP, are reversible inhibitors of alcohol dehydrogenase (ADH) class I isozymes. The Ki of daidzein for r.sub.1 r.sub.1 and r.sub.2 r.sub.2 ADH isozymes is about 1 .mu.M. The inhibition is competitive with respect to ethanol, but uncompetitive with respect to NAD (W-M Keung and B. L. Vallee, Alcohol Clin. Exp. Res. 17(6) 1254, 1993; i.b.d. Prod. Natl. Acad. Sci USA 90, 1247, 1993). They reported that daidzin did not inhibit ADH; it was, however, a potent inhibitor of aldehyde dehydrogenase (ALDH) II and II of human mitochondria. They further suggested that the isoflavones could stimulate ethanol oxidation by increasing NAD.sup.+ regeneration via accelerated respiration because daidzein and several other isoflavones exerted significant uncoupling effect of oxidative phosphorylation in vitro with resting state mitochondria. (J. J. O. Lundh and B. O. Lundgren, J. Agricult, Food Chem. 39: 736, 1991).